Intracellular receptors (IR) form a class of structurally related gene regulators known as xe2x80x9cligand dependent transcription factorsxe2x80x9d (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell""s DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound that inhibits the effect of the hormone is an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist, alternatively they may be used in conjunction with a PR antagonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus that can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces or ablates that risk.
Jones et al (U.S. Pat. No. 5,688,810) is the PR antagonist dihydroquinoline A. 
Jones et al described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand. 
Jones et al (U.S. Pat. No. 5,688,810) described the PR antagonist dihydroquinoline A. 
Zhi et al described lactones D, E and F as PR antagonists (J. Med. Chem. 41, 291, 1998). 
Zhi et al described the ether G as a PR antagonist (J. Med. Chem. 41, 291, 1998). 
Combs et al disclosed the amide H as a ligand for the PR (J. Med. Chem. 38, 4880, 1995). 
Perlman et al described the vitamin D analog I as a PR ligand (Tetrahedron. Lett. 35, 2295, 1994). 
Hamann et al described the PR antagonist J (Ann. N.Y. Acad. Sci. 761, 383, 1995). 
Chem et al described the PR antagonist K (Chen et al, POI-37, 16th Int. Cong. Het. Chen, Montana, 1997). 
Kurihari et al described the PR ligand L (J. Antibiotics 50, 360, 1997). 
Kuhla et al claimed the oxindole M as a cardiotonic (WO 86/03749). 
Weber claimed the oxindole N for cardiovascular indications (WO 91/06545). 
Fischer et al claim a preparation for making compounds which include the generic structure O (U.S. Pat. No. 5,453,516). 
Singh et al described the PDE III inhibitor P (J. Med. Chem. 37, 248, 1994). 
Andreani et al described the cytotoxic agent Q (Acta. Pharn. Nord. 2, 407, 1990). 
Binder et al described structure R which is an intermediate for preparing COX II inhibitors (WO 97/13767). 
Walsh (A. H. Robins) described the oxindole S as an intermediate (U.S. Pat. Nos. 4,440,785, 4,670,566). 
R1=F, Cl, Br, alky, NH2 
R2=alkyl, alkoxy, F, Cl, NH2, CF3.
Bohm et al claim the oxindole T as cardiovascular agents (WO 91/06545). 
Bohm et al include the generic structure U (WO 91/04974). 
A Japanese patent contains the generic structure V (JP 63112584 A). 
Boar et al described the dioxolane W as an intermediate for preparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1). 
Kende et al described methodology for preparing 3,3-substituted oxindoles, e.g., X, that was utilized in the present invention (Synth. Commun. 12, 1, 1982). 
There are numerous literature reports that disclose a number of benzoxazin-2-ones. However, none of these examples in these patents contain substituents necessary for the compounds to be active as progesterone receptor modulators.
Among these publications, Narr et al (German Patent, DE 3633861, CA 109:22973) claimed that imidazobenzoxazinones, e.g. Y, as cardotonics; Benzoxazin-2-ones, such as brofoxine (Z), being active as an anxiolytic was reported by Hartmann et al (Proc. West. Pharmacol. Soc. 21, 51-55(1978)). More recently, a number of patents (e.g., Young et al WO95/20389; Christ et al. WO98/14436) claimed quinazolin-2-ones and benzoxazin-2-ones such as compounds AA and BB as inhibitors of HIV reverse transcriptase. 
This invention provides progesterone receptor agonists of Formula 1 having the structure 
wherein
T is O, S, or absent;
R1, and R2 are each, independently, hydrogen, alky, substituted alkyl; or
R1 and R2 are taken together form a ring and together contain xe2x80x94CH2(CH2)nCH2xe2x80x94, xe2x80x94CH2CH2CMe2CH2CH2xe2x80x94, xe2x80x94O(CH2)pCH2xe2x80x94, xe2x80x94O(CH2)qOxe2x80x94, xe2x80x94CH2CH2OCH2CH2xe2x80x94, or xe2x80x94CH2CH2NR7CH2CH2xe2x80x94;
n=1-5;
p=1-4;
q=1-4
R3 is hydrogen, OH, NH2, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or CORA;
RA is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R4 is hydrogen, halogen, CN, NH2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R5 is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, substituted alkyl, or CORB;
RB is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R7 is hydrogen or alkyl;
or a pharmaceutically acceptable salt thereof, which are useful for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
Preferred compounds of this invention are those having the structure: 
wherein
T is O, or absent;
R1, and R2 are each, independently, hydrogen, alkyl, substituted alkyl; or
R1 and R2 are taken together form a ring and together contain xe2x80x94CH2(CH2)nCH2xe2x80x94;
n=1-5;
R3 is hydrogen;
R4 is hydrogen or halogen;
R5 is hydrogen or alkyl;
R6 is hydrogen or alkyl;
or a pharmaceutically acceptable salt thereof.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereoisomers. While shown without respect to stereochemistry in Formula 1, the present invention includes such optical isomers and diastereoisomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonists in functional models, either/or in-vitro and in-vivo. These compounds may be used for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
The term xe2x80x9calkylxe2x80x9d is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1-6 carbon atoms; xe2x80x9calkenylxe2x80x9d includes both straight- and branched-chain alkyl groups of 2-6 carbon atoms containing at least one carbon-carbon double bond; xe2x80x9calkynylxe2x80x9d group includes both straight- and branched-chain alkyl groups of 2-6 carbon atoms with at least one carbon-carbon triple bond.
The terms xe2x80x9csubstituted alkylxe2x80x9d. xe2x80x9csubstituted alkenylxe2x80x9d, and xe2x80x9csubstituted alkynylxe2x80x9d refer to alkyl, alkenyl, and alkynyl as containing one or more substituents from the group including halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term xe2x80x9cthioalkylxe2x80x9d is used herein to refer to the SR group, where R is alkyl or substituted alkyl.
The term xe2x80x9calkoxyxe2x80x9d is used herein to refer to the OR group, where R is alkyl or substituted alkyl.
The term xe2x80x9caryloxyxe2x80x9d is used herein to refer to the OR group, where R is aryl or substituted aryl.
The term xe2x80x9calkylcarbonylxe2x80x9d is used herein to refer to the RCO group, where R is alkyl or substituted alkyl.
The term xe2x80x9calkylcarboxyxe2x80x9d is used herein to refer to the COOR group, where R is alkyl or substituted alkyl. This term is also referred to as alkoxycarbonyl.
The term xe2x80x9caminoalkylxe2x80x9d refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups may be either same or different and the point of attachment is on the nitrogen atom.
The term xe2x80x9chalogenxe2x80x9d is defined as Cl, Br, F, and I.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids. Salts may also be formed from inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, and organic bases, such as ammonium, mono-, di-, and trimethylammonium, mono-, di- and triethylammonium, mono-, di- and tripropylammonium (iso and normal), ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-iso-propylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butyl piperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium, ethyl diethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium, phenylmonoethanolammonium, and the like.
The compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention. 
According to scheme 1, commercially available oxindole 4 is treated with a strong organo-metallic base (e.g., butyl lithium lithium diisopropylamide, potassium hexamethyldisilazide) in an inert solvent (e.g. THF, diethyl ether) under nitrogen at reduced temperature (ca. xe2x88x9220xc2x0 C.) (Kende, et al, Synth. Commun. 12, 1, 1982). The resulting di-anion then is treated with excess electrophile such as an alkyl halide, preferably an iodide. If R1 and R2 are to be joined such as the product 5 contains a spirocycle at position 3, then the electrophile should be bifunctional, i.e. a diiodide. Subsequent bromination of 5 proceeds smoothly with bromine in acetic acid (an organic co-solvent such as dichloromethane may be added as required) in the presence of sodium acetate, to afford the aryl bromide 6. The bromide 6 is reacted with a palladium salt (e.g., tetrakis(triphenylphoshine)palladium(0) or palladium acetate), in a suitable solvent (e.g., THF, dimethoxyethane, acetone, ethanol or toluene) at room temperature under an inert atmosphere (argon, nitrogen). The mixture is then treated with pyrrole 2-boronic acid (Synthesis 613, 1991) and a base (potassium carbonate, triethylamine, potassium phosphate) in water or fluoride source (cesium fluoride) under anhydrous conditions. Treatment of the biaryl compound 7 with chlorosulfonyl isocyanate followed by an excess of DMF at low temperature produces the protected cyanopyrrole 8. Removal of the tert-butyloxycarbonyl (BOC) protecting group via standard conditions (e.g., TFA/dichloromethane, aqueous NaOH, thermolysis) produces the required final product which is purified by standard means. 
As depicted in Scheme 2, an appropriately substituted ortho-amino benzoic acid, or derivative (such as ethyl ester) 10 is treated with a suitable organometallic reagent, e.g., Grignard reagent, in appropriate nonprotic solvents (e.g., THF, ether, toluene) under an inert atmosphere such as argon or nitrogen at xe2x88x9278xc2x0 C. to room temperature to give ortho-amino carbinol 11. Ring closure of carbinol 11 to yield benzoxazin-2-ones 12 is commonly effected by a condensing agent (e.g., carbonyldiimidazole, phosgene, dimethylcarbonate, diethylcarbonate) in a suitable nonprotic solvent (e.g., THF, ether, toluene) at temperatures in the range of room temperature to 65xc2x0 C. The pyrrole ring is attached to this platform by employing a suitable coupling reaction (e.g., Suzuki, Stille) to give the biaryl 13. These reactions are performed in the presence of suitable catalyst (e.g., palladium or nickel complexes often with phosphino ligands, e.g., Ph3P, dppf, dppe or palladium salts such as palladium acetate) and a base: the commonly used bases include (but are not limited to) sodium bicarbonate, sodium carbonate, potassium phosphate, barium carbonate, potassium acetate, or cesium fluoride. The most commonly used solvents in these reactions include benzene, DMF, isopropanol, ethanol, DME, ether, acetone or a mixture of any one of these solvent and water. The coupling reaction generally is executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from room temperature to 95xc2x0 C. Treatment of the biaryl compound 13 with chlorosulfonyl isocyanate followed by an excess of DMF at low temperature produces the protected cyanopyrrole 14. Removal of the tert-butyloxycarbonyl (BOC) protecting group via standard conditions (e.g., TFA/dichloromethane, aqueous NaOH, thermolysis) produces the required final product 15 which is purified by standard means.
The compounds of this invention are progestational agonists, and are therefore useful as oral contraceptives (male and female), in hormone replacement therapy (particularly when combined with an estrogen), in the treatment of endometriosis, luteal phase defects, benign breast and prostatic diseases and prostatic, breast, ovarian, uterine and endometrial cancers.
The compounds of this invention can be used alone as a sole therapeutic agent or can be used in combination with other agents, such as other estrogens, progestins, or androgens.
The compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. The pharmaceutical carrier may be solid or liquid.
A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds of this invention can also be administered orally either in liquid or solid composition form.
The compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
The dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0.02 xcexcg/kg-750 xcexcg/kg. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached; precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated. Preferably, the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, pre filled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The following provides the preparation of representative compounds of this invention.